Dornase alfa. A review of pharmacoeconomic and quality-of-life aspects of its use in cystic fibrosis

Cystic fibrosis (CF) is a fatal hereditary disease; patients with CF have an average lifespan of 30 years. By cleaving neutrophil-derived DNA, dornase alfa (recombinant human deoxyribonuclease I) decreases the adhesiveness and visco-elasticity of sputum in the infected lungs of patients with CF. As a result, respiratory function is improved in patients with all degrees of disease severity, and the relative risk of pulmonary exacerbations is reduced in patients with mild to moderate disease. Resource utilisation (days spent in hospital or receiving parenteral antibiotics) in patients with mild to moderate disease is also reduced by dornase alfa, as evidenced by a placebo-controlled trial in > 900 patients. Cost savings generated by these reductions in resource use during 24 weeks of dornase alfa therapy offset about 17 to 37.5% of the acquisition cost of the drug, depending on local cost data for various countries. Reductions in resource utilisation with dornase alfa have not been observed in patients with severe disease. Available cost-effectiveness and cost-utility analyses are not fully published. One analysis estimated that the incremental cost of avoiding one hospitalisation was about $Can 15,000 relative to standard therapy after 1 year of treatment. Informal analysis in the UK suggests a cost per quality-adjusted life-year of 25,000 Pounds for dornase alfa. Some quality-of-life (QOL) domains (mainly cough frequency and chest congestion) have shown modest improvement in patients treated with dornase alfa, mainly those with mild CF. Persuasive evidence of QOL benefit is lacking in those with more severe disease. Identifying patients most likely to benefit from dornase alfa therapy is essential to maximise clinical and cost benefits. The lack of a demonstrated reduction in resource utilisation in patients with severe CF makes its use more difficult to justify economically in this group than in those with less severe disease. However, in the absence of other treatments for this group, economic considerations must be weighed against clinical benefits. In conclusion, the acquisition cost of dornase alfa is partially offset by savings gained by reducing resource utilisation in patients with mild to moderate CF, and the drug appears to improve quality of life in some patients, mostly those with less severe disease. However, in the absence of guidance from definitive cost-effectiveness analyses, individual healthcare providers must make their own decisions about how best to provide dornase alfa to patients with CF in a rational and cost-justifiable manner.     

Iso-electric focusing of aqueous humour IgG in multiple sclerosis

Samples of aqueous fluid were obtained from 35 controls who were people undergoing routine cataract surgery. Similar samples were taken from seven patients with clinically definite multiple sclerosis (MS) and a previous history of optic neuritis, either at cataract surgery or as an elective procedure. Oligoclonal bands were found in only one subject who suffered from the MS-uveitis syndrome.     

Discriminated conditioned taste aversion for studying multi-element stimulus control

The effects of morphine pre-treatment interval on the stimulus control exerted by a multi-element stimulus consisting of morphine (5.6mg/kg), saccharin (0.2%, w/v), and a ball-bearing drinking nozzle in a discriminated taste aversion procedure were examined. In this discriminated aversion procedure, rats received injections of LiCI following presentation of this multielement stimulus, and injections of saline following the saline, water, and non-ball-bearing nozzle composite stimulus. These paired rats were compared to unpaired rats that received saline injections rather than LiCI injections following presentation of the multi-element stimulus. Morphine pre-treatment times of 5, 10, and 20min were examined in groups of 12 paired and 6 unpaired rats. The discrimination was rapidly learned under all three pre-treatment intervals. In subsequent testing with each individual stimulus element and combinations of two stimulus elements, stimulus control was clearly exerted by both morphine and saccharin. Paired rats drank less saccharin than unpaired rats, and less saccharin than water. Similarly, paired rats drank less fluid following morphine administration than following saline administration, and less fluid than unpaired rats following morphine administration. Control by the nozzle type was also apparent in significant interactions between the nozzle and morphine or saccharin and pairing with LiCI. In general, pre-treatment time did not influence the stimulus control that developed. However, at the two shorter pre-treatment times there was some indication that a conditioned taste aversion to morphine was developing in the unpaired rats. These experiments indicate that such discriminated taste aversion procedures may be viable methods for studying the contextual control of how drugs function as discriminative stimuli, and that longer drug pre-treatment times may be desirable in such procedures.     

Linked suppression in peripheral T cell tolerance to the house dust mite derived allergen Der p 1

BACKGROUND: Peripheral tolerance is required to maintain balance within the immune system. A feature of peripheral tolerance is linked suppression, in which tolerance induced to a single T cell epitope inhibits the response to all epitopes in the same protein. It is suggested that this phenomenon is mediated by regulatory T cells through either the activity of immunopressive cytokines or direct cell contact. In previous experiments we failed to detect inhibitory cytokines when T cells from mice rendered tolerant by intranasal delivery of the immunodominant peptide of Der p 1 (p 1, 110-131) were restimulated with peptide in vitro. Therefore, the aim of this study was to determine if cognate interactions between T cells mediated by Notch/Delta signaling induce and maintain peripheral T cell tolerance. METHODS: Using in situ hybridization and viral mediated gene transfer, the expression and function of Delta1 were investigated in a murine model of T cell tolerance to Der p 1 in vivo. RESULTS: Delta1 expression is increased on peripheral T cells during the induction of tolerance with high-dose peptide delivered intranasally and when tolerant animals are rechallenged under immunogenic conditions. Peptide p 1, 110-131-specific CD4+ T cells transfected with Delta1 inhibited the response of antigen-primed T cells and induced linked suppression. CONCLUSIONS: High-dose peptide delivered intranasally induces transient expression of Delta 1 on inhibitory CD4+ T cells. Ligation of the Notch1 receptor on neighbouring T cells by Delta1+ regulatory T cells inhibits clonal expansion of the former and mediates linked suppression.     

Gender and age-related differences in the pattern of complete denture referrals from general dental practitioners

This study was designed to identify gender and age-related differences among complete denture referrals from general dental practice to a dental teaching hospital over a 4 year period. Referral rates were calculated according to male/female ratios in the edentulous population. Although more women than men were referred overall, the proportion of males to females referred was similar to that in the edentulous population. Significant gender-related differences in referral patterns were identified, suggesting that edentulous males with complete denture problems, and aged 69 or less, made proportionately less use of hospital services, and proportionately more when aged 70 or over.     

Infection, immunisation and atherosclerosis: is there a link?

Atherosclerosis is the predominant underlying pathology responsible for coronary heart disease (CHD). It bears all the hallmarks of a chronic inflammatory disease and typical atherosclerotic lesions contain activated macrophages and T-cells. There have been several reports of possible associations between prior exposure to a number of specific micro-organisms and subsequent CHD, and prospective epidemiological studies have reported that elevated plasma levels of particular acute phase reactants (APRs) are predictors of future cardiac events. Investigators have also shown that immunisations exacerbate atherosclerosis in experimental animal models. These data raise the possibility that immunostimulation associated with natural infection by certain organisms, or vaccination, may promote atherosclerosis. A hypothesis which may explain all these findings, is that the cellular--and perhaps humoral--responses associated with immune stimulation may enhance atherogenesis.     

Quinupristin/dalfopristin: a review of its use in the management of serious gram-positive infections

Quinupristin/dalfopristin is the first parenteral streptogramin antibacterial agent, and is a 30:70 (w/w) ratio of 2 semisynthetic pristinamycin derivatives. The combination has inhibitory activity against a broad range of gram-positive bacteria including methicillin-resistant staphylococci, vancomycin-resistant Enterococcus faecium (VREF), drug-resistant Streptococcus pneumoniae, other streptococci, Clostridium perfringens and Peptostreptococcus spp. The combination also has good activity against selected gram-negative respiratory tract pathogens including Moraxella catarrhalis, Legioniella pneumophila and Mycoplasma pneumoniae. Quinupristin/dalfopristin has poor activity against E. faecalis. The combination is bactericidal against staphylococci and streptococci, although constitutive erythromycin resistance can affect its activity. As for many other agents, quinupristin/dalfopristin is generally bacteriostatic against E. faecium. In patients with methicillin-resistant S. aureus (MRSA) or VREF infections participating in prospective emergency-use trials, quinupristin/dalfopristin 7.5 mg/kg every 8 or 12 hours achieved clinical or bacteriological success in > or =64% of patients. Emergence of resistance to quinupristin/dalfopristin was uncommon (4% of patients) in those with VREF infections. Quinupristin/dalfopristin 7.5 mg/kg 8- or 12-hourly also achieved similar clinical success rates to comparator agents in patients with presumed gram-positive complicated skin and skin structure infections or nosocomial pneumonia (administered in combination with aztreoman) in 3 large multicentre randomised trials. Systemic adverse events associated with quinupristin/dalfopristin include gastrointestinal events (nausea, vomiting and diarrhoea), rash and pruritus. Myalgias and arthralgias also occur at an overall incidence of 1.3%, although higher rates (2.5 to 31%) have been reported in patients with multiple comorbidities. Venous events are common if the drug is administered via a peripheral line; however, several management options (e.g. use of central venous access, increased infusion volume) may help to minimise their occurrence. Hyperbilirubinaemia has been documented in 3.1% of quinupristin/dalfopristin recipients versus 1.3% of recipients of comparator agents. Quinupristin/dalfopristin inhibits cytochrome P450 3A4 and therefore has the potential to increase the plasma concentrations of substrates of this enzyme. CONCLUSIONS: Quinupristin/dalfopristin, the first parenteral streptogramin, offers a unique spectrum of activity against multidrug-resistant gram-positive bacteria. In serious gram-positive infections for which there are other treatment options available, the spectrum of activity and efficacy of quinupristin/ dalfopristin should be weighed against its tolerability and drug interaction profile. However, in VREF or unresponsive MRSA infections, where few proven treatment options exist, quinupristin/dalfopristin should be considered as a treatment of choice for these seriously ill patients.     

The pathogenesis of Dieulafoy's gastric erosion

The solitary gastric erosion of Dieulafoy is rarely recognized but is not an uncommon cause of massive upper gastrointestinal hemorrhage. The English literature has only recently described this lesson in vivo. Its etiology and pathogenesis has remained poorly defined since first described in 1896. We have recently studied a series of nine cases (the largest English literature series), five of which were recognized and diagnosed at operation. Multiple tissue staining techniques were used to study the biopsy specimens for "clues" as to the pathogenesis of this lesion to be a vascular dysplasia that is associated with chronic gastritis and that thrombosis and necrosis of the abnormally tortuous submucosal artery occurs before perforation and exigent bleeding. The total lack of inflammatory reaction at the base of the lesion precludes a diagnosis of "ulceratio simplex" as originally described.     

Leisure-time physical activity as an estimate of physical fitness: a validation study

This paper describes a new interview questionnaire for the assessment of leisure-time physical activity (LTPA), and its validation as an alternative estimate of physical fitness. British subjects (77 males, 41 females) provided details of their LTPA over a period of a "typical" 2 weeks, enabling the estimation of the energy expended. Physical fitness was assessed with a battery of measures, the optimal single measure being sub-maximal physical work capacity (PWC). The questionnaire showed LTPA to be stable following test-retest administration (r = 0.86; p less than 0.0001) for total LTPA energy expenditure. Total LTPA was found to be significantly related to PWC (r = 0.48, p less than 0.0001), as were very hard (r = 0.55; p less than 0.0001) and hard LTPA (r = 0.38; p less than 0.0001). Multiple regression analysis with PWC as the dependent variable yielded a multiple correlation of r = 0.87, with significant contributions from very hard and hard LTPA. It is concluded that whilst this questionnaire is both reliable and a valid estimate of physical fitness amongst a population consistent in their leisure-time physical activities, there is scope for its further use within larger populations, allowing for an analysis of the effects of age and gender on the associations so far observed.